dbSNP rs587782221: NBN:p.Lys622Asn (chr8-89947872-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002485.5(NBN):c.1866G>T(p.Lys622Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K622R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

Publications

0 publications found

Variant links:

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
idiopathic aplastic anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1866G>T	p.Lys622Asn	missense_variant	Exon 12 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1866G>T	p.Lys622Asn	missense_variant	Exon 12 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1422722

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708270

African (AFR)

AF:

0.00

AC:

AN:

32478

American (AMR)

AF:

0.00

AC:

AN:

43694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25376

East Asian (EAS)

AF:

0.00

AC:

AN:

39126

South Asian (SAS)

AF:

0.00

AC:

AN:

83682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081716

Other (OTH)

AF:

0.00

AC:

AN:

58800

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.076

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

1.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.56

N;N;.

REVEL

Benign

0.037

Sift

Benign

0.073

T;T;.

Sift4G

Benign

0.47

T;T;T

Polyphen

0.44

B;.;.

Vest4

0.39

MutPred

0.32

Gain of loop (P = 0.0045);.;.;

MVP

0.78

MPC

0.16

ClinPred

0.65

GERP RS

5.1

Varity_R

0.086

gMVP

0.11

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over